What pharmacologic agents are used to reverse anticholinergic toxicity, including the first‑line drug, its dosing and contraindications, and alternative treatments?

Reversal of Anticholinergic Toxicity

Physostigmine is the first-line antidote for reversing anticholinergic toxicity, administered intravenously at 2 mg for adults and 0.02 mg/kg for children, with dramatic reversal of symptoms expected within minutes. 1, 2

First-Line Treatment: Physostigmine

Mechanism and Efficacy

• Physostigmine is a reversible anticholinesterase that increases acetylcholine concentration at cholinergic transmission sites by inhibiting acetylcholinesterase 2
• As a tertiary amine, it readily crosses the blood-brain barrier and reverses both central and peripheral anticholinergic effects, unlike quaternary ammonium compounds such as neostigmine 2, 3
• Dramatic symptom reversal occurs within minutes of intravenous administration if the diagnosis is correct and the patient has not suffered anoxia 2

Dosing Protocol

• Adults: 2 mg IV initially 1
• Children: 0.02 mg/kg IV 1
• Administer slowly intravenously, preferably over several minutes 2
• Duration of action is relatively short at 45-60 minutes, requiring repeated doses as clinically necessary 1, 2

Clinical Presentation Requiring Treatment

The anticholinergic toxidrome includes:

• Central effects: Anxiety, delirium, disorientation, hallucinations, hyperactivity, seizures, and potentially coma with medullary paralysis 2
• Peripheral effects: Tachycardia, hyperpyrexia, mydriasis, vasodilation, urinary retention, diminished gastrointestinal motility, decreased secretions in salivary/sweat glands, and loss of respiratory secretions 2

Contraindications and Precautions

• Avoid in patients with asthma, gangrene, cardiovascular disease, or mechanical obstruction of the gastrointestinal or genitourinary tract 2
• Risk of seizures exists, particularly with rapid administration or in patients with underlying seizure disorders 4
• Monitor closely for cholinergic crisis (excessive salivation, bradycardia, bronchospasm) indicating overdose 2

Evidence for Efficacy

• Patients receiving physostigmine alone had significantly lower intubation rates (1.9% vs 8.4%) compared to other treatments 5
• Medical toxicologists use physostigmine in 12.4% of anticholinergic toxicity cases as monotherapy, with an additional 8.8% receiving combination therapy with benzodiazepines 5

Alternative Treatment: Rivastigmine

When to Consider

• Use rivastigmine when physostigmine is unavailable due to national shortage 6
• Rivastigmine is another reversible acetylcholinesterase inhibitor that crosses the blood-brain barrier and has demonstrated effectiveness in limited case reports 6

Dosing Options

• Oral/nasogastric: 3 mg every hour until symptom resolution 6
• Transdermal patch: Provides consistent 24-hour drug absorption, applied after initial stabilization in consultation with toxicology 6
• Case reports demonstrate return to baseline within 27 hours using this approach 6

Adjunctive Therapy

Benzodiazepines

• Administer 0.05-0.1 mg/kg midazolam or 0.2 mg/kg diazepam IV/IM in fractionated doses 1
• Use to reduce anxiety, control seizures, and facilitate mechanical ventilation 1
• Benzodiazepines alone were used in 28.7% of anticholinergic toxicity cases but had higher intubation rates than physostigmine 5

Supportive Care

• Continuous cardiac, neurological, and respiratory monitoring is essential 7
• Maintain airway patency and provide mechanical ventilation if needed 1
• Address hyperthermia, fluid status, and urinary retention as they arise 2

Critical Clinical Pitfalls

• Never use antipsychotics for anticholinergic delirium, as they may worsen the toxidrome and were used in only 2.7% of cases 5
• Physostigmine's short duration of action (45-60 minutes) necessitates repeated dosing—do not assume a single dose provides lasting reversal 2
• Ensure correct diagnosis before administering physostigmine, as it can cause cholinergic crisis if given inappropriately 2
• Benzodiazepines alone do not address the underlying pathophysiology and result in higher intubation rates 5